Based on gain- or loss-of-function data collected in animal disease models using genetics or pharmacological modulation of microRNAs (miRNAs), it is now well accepted that miRNAs are important players during disease. These studies, combined with recent positive clinical efficacy data (Janssen et al, 2013), underscore the relevance of miRNAs and the viability for miRNAs to become the next class of therapeutics. Indeed, miRNAs have several advantages as therapeutic intervention points in that they are small and comprise a known sequence. Additionally, since a single miRNA can regulate numerous target mRNAs within biological pathways, modulation of a miRNA in principle allows for influencing an entire gene network and modifying complex disease phenotypes (van Rooij & Olson, 2012).
While many studies have shown therapeutic efficacy using single-stranded miRNA inhibitors called antimiRs, efforts to restore or increase the function of a miRNA have been lagging behind (van Rooij et al, 2012). Currently, miRNA function can be increased either by viral overexpression or by using synthetic double-stranded miRNAs. So far the use of adeno-associated viruses (AAV) to drive expression of a given miRNA for restoring its activity in vivo has shown to be effective in a mouse model of hepatocellular and lung carcinoma (Kasinski & Slack, 2012; Kota et al, 2009) and spinal and bulbar muscular atrophy (Miyazaki et al, 2012), while the use of unformulated synthetic oligonucleotide-based approaches to increase miRNA levels has not been well explored.
The microRNA-29 (miR-29) family is well characterized for their ability to regulate extracellular matrix proteins (He et al, 2013). The family consists of miR-29a, -29b and -29c, which are expressed as two bicistronic clusters (miR-29a/-29b-1 and miR-29b-2/-29c), and are largely homologous in sequence with only a few mismatches between the different members in the 3′ regions of the mature miRNA (van Rooij et al, 2008). All three members are reduced in different types of tissue fibrosis and therapeutic benefit of increasing miR-29 levels has been shown for heart (van Rooij et al, 2008), kidney (Qin et al, 2011; Wang et al, 2012; Xiao et al, 2012), liver (Roderburg et al, 2011; Sekiya et al, 2011; Zhang et al, 2012), lung (Cushing et al, 2011; Xiao et al, 2012) and systemic sclerosis (Maurer et al, 2010).
There is a need in the art for synthetic oligonucleotide mimics of miR-29 that can effectively increase miR-29 activity in vivo. Such miR-29 mimics or miR-29 promiRs are useful for treating various tissue fibrotic conditions.